Caracterización fenotípica y seguimiento endoscópico del síndrome de poliposis serrada

El cáncer colorrectal (CCR) es el tercer tumor maligno más incidente a nivel mundial y el primero en España si consideramos ambos sexos, y conlleva una elevada morbi-mortalidad. A pesar de que durante décadas se asumió que prácticamente la única lesión precursora del CCR era el adenoma colorrectal, desde hace 15–20 años se sabe que también los pólipos serrados (PS) pueden malignizar –en este caso, a través de la vía serrada de la carcinogénesis–, siendo el origen del 25–30% de los CCR esporádicos. El síndrome de poliposis serrada (SPS) –que es la poliposis de colon más prevalente– es una entidad caracterizada por la existencia de PS múltiples y/o de gran tamaño a lo largo de todo el colon, y se define según la OMS (2010) por la presencia de uno o más de los siguientes criterios diagnósticos: 1) al menos cinco PS proximales al colon sigmoide, de los cuales dos o más debían ser mayores de 10 mm; o 2) cualquier número de PS proximales al colon sigmoide en un paciente con un familiar de primer grado diagnosticado de SPS; o 3) más de 20 PS de cualquier tamaño, distribuidos a lo largo de todo el colon. El SPS se asocia a un riesgo aumentado de CCR (15,8–36,7%) con respecto a la población general. No obstante, se ha demostrado que tras extirpar todos los pólipos existentes en el momento del diagnóstico (lo que se ha denominado “clearance”) y bajo un estrecho seguimiento endoscópico, el riesgo de CCR está sólo ligeramente elevado (incidencia acumulada entre 0 y 7% a los cinco años)..

Density functional study of the magnetic properties of Bi4Mn clusters: Discrepancy between theory and experiment

We have performed collinear and noncollinear calculations on neutral Bi4Mn and collinear ones on ionized Bi4Mn with charges +1 and −1 to find out why theoretical calculations will not predict the magnetic state found in the experiment. We have used the density functional theory to find a fit between the theoretical prediction of the magnetic moment and the experimental value. Our calculations have consisted in a structural search of local energy minima, and the lowest energy magnetic state for each resulting isomer. The geometry optimization found three local minima whose fundamental state is the doublet spin state. These isomers could not be found in previous theoretical works, but they are higher in energy than the lowest-lying isomer by ≈1.75 eV. This magnetic state could help understand the experiment. Calculations of noncollinear magnetic states for the Bi4Mn do not lower the total magnetic moment. We conclude arguing how the three isomers with doublet state could actually be the ones measured in the experimentThis research has been done under the Projects No. MAT2009-08165 and No. INCITE08PXIB236052PR. One of the authors has been enjoying financial support from the Isabel Barreto programS

Predictive Value of Carcinoembryonic Antigen in Symptomatic Patients without Colorectal Cancer: A Post-Hoc Analysis within the COLONPREDICT Cohort

We aimed to assess the risk of cancer in patients with abdominal symptoms after a complete colonoscopy without colorectal cancer (CRC), according to the carcinoembryonic antigen (CEA) concentration, as well as its diagnostic accuracy. For this purpose, we performed a post-hoc analysis within a cohort of 1431 patients from the COLONPREDICT study, prospectively designed to assess the fecal immunochemical test accuracy in detecting CRC. Over 36.5 ± 8.4 months, cancer was detected in 115 (8%) patients. Patients with CEA values higher than 3 ng/mL revealed an increased risk of cancer (HR 2.0, 95% CI 1.3–3.1), CRC (HR 4.4, 95% CI 1.1–17.7) and non-gastrointestinal cancer (HR 1.7, 95% CI 1.0–2.8). A new malignancy was detected in 51 (3.6%) patients during the first year and three variables were independently associated: anemia (OR 2.8, 95% CI 1.3–5.8), rectal bleeding (OR 0.3, 95% CI 0.1–0.7) and CEA level >3 ng/mL (OR 3.4, 95% CI 1.7–7.1). However, CEA was increased only in 31.8% (95% CI, 16.4–52.7%) and 50% (95% CI, 25.4–74.6%) of patients with and without anemia, respectively, who would be diagnosed with cancer during the first year of follow-up. On the basis of this information, CEA should not be used to assist in the triage of patients presenting with lower bowel symptoms who have recently been ruled out a CRCThis work was supported by Spain’s Carlos III Healthcare Institute by means of project PI17/00837 (Co-funded by European Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future

SHARDS frontier fields: physical properties of a low-mass Lyα emitter at z = 5.75

We analyze the properties of a multiply-imaged Lyman-alpha (Lya) emitter at z=5.75 identified through SHARDS Frontier Fields intermediate-band imaging of the Hubble Frontier Fields (HFF) cluster Abell 370. The source, A370-L57, has low intrinsic luminosity (M_UV~-16.5), steep UV spectral index (\beta=-2.4+/-0.1), and extreme rest-frame equivalent width of Lya (EW(Lya)=420+180-120 \AA). Two different gravitational lens models predict high magnification (\mu~10--16) for the two detected counter-images, separated by 7", while a predicted third counter-image (\mu~3--4) is undetected. We find differences of ~50% in magnification between the two lens models, quantifying our current systematic uncertainties. Integral field spectroscopy of A370-L57 with MUSE shows a narrow (FWHM=204+/-10 km/s) and asymmetric Lya profile with an integrated luminosity L(Lya)~10^42 erg/s. The morphology in the HST bands comprises a compact clump (r_e<100 pc) that dominates the Lya and continuum emission and several fainter clumps at projected distances <1 kpc that coincide with an extension of the Lya emission in the SHARDS F823W17 and MUSE observations. The latter could be part of the same galaxy or an interacting companion. We find no evidence of contribution from AGN to the Lya emission. Fitting of the spectral energy distribution with stellar population models favors a very young (t<10 Myr), low mass (M*~10^6.5 Msun), and metal poor (Z<4x10^-3) stellar population. Its modest star formation rate (SFR~1.0 Msun/yr) implies high specific SFR (sSFR~2.5x10^-7 yr^-1) and SFR density (Sigma_SFR ~ 7-35 Msun/yr/kpc^2). The properties of A370-L57 make it a good representative of the population of galaxies responsible for cosmic reionization.Comment: 14 pages, 8 figures, 4 tables. Accepted for publication in Ap

Development and external validation of a faecal immunochemical test-based prediction model for colorectal cancer detection in symptomatic patients

Background: Risk prediction models for colorectal cancer (CRC) detection in symptomatic patients based on available biomarkers may improve CRC diagnosis. Our aim was to develop, compare with the NICE referral criteria and externally validate a CRC prediction model, COLONPREDICT, based on clinical and laboratory variables. Methods: This prospective cross-sectional study included consecutive patients with gastrointestinal symptoms referred for colonoscopy between March 2012 and September 2013 in a derivation cohort and between March 2014 and March 2015 in a validation cohort. In the derivation cohort, we assessed symptoms and the NICE referral criteria, and determined levels of faecal haemoglobin and calprotectin, blood haemoglobin, and serum carcinoembryonic antigen before performing an anorectal examination and a colonoscopy. A multivariate logistic regression analysis was used to develop the model with diagnostic accuracy with CRC detection as the main outcome. Results: We included 1572 patients in the derivation cohort and 1481 in the validation cohorts, with a 13.6 % and 9. 1 % CRC prevalence respectively. The final prediction model included 11 variables: age (years) (odds ratio [OR] 1.04, 95 % confidence interval [CI] 1.02-1.06), male gender (OR 2.2, 95 % CI 1.5-3.4), faecal haemoglobin >= 20 mu g/g (OR 17.0, 95 % CI 10.0-28.6), blood haemoglobin = 3 ng/mL (OR 4.5, 95 % CI 3.0-6.8), acetylsalicylic acid treatment (OR 0.4, 95 % CI 0.2-0.7), previous colonoscopy (OR 0.1, 95 % CI 0.06-0.2), rectal mass (OR 14.8, 95 % CI 5.3-41.0), benign anorectal lesion (OR 0.3, 95 % CI 0.2-0.4), rectal bleeding (OR 2.2, 95 % CI 1.4-3.4) and change in bowel habit (OR 1.7, 95 % CI 1.1-2.5). The area under the curve (AUC) was 0.92 (95 % CI 0.91-0.94), higher than the NICE referral criteria (AUC 0.59, 95 % CI 0.55-0.63; p < 0.001). On the basis of the thresholds with 90 % (5.6) and 99 % (3.5) sensitivity, we divided the derivation cohort into three risk groups for CRC detection: high (30.9 % of the cohort, positive predictive value [PPV] 40.7 %, 95 % CI 36.7-45.9 %), intermediate (29.5 %, PPV 4.4 %, 95 % CI 2.8-6.8 %) and low (39.5 %, PPV 0.2 %, 95 % CI 0.0-1.1 %). The discriminatory ability was equivalent in the validation cohort (AUC 0.92, 95 % CI 0.90-0.94; p = 0.7). Conclusions: COLONPREDICT is a highly accurate prediction model for CRC detection.This study was funded by a grant from Instituto de Salud Carlos III (PI11/00094). JC and VH have received an intensification grant through the European Commission funded "BIOCAPS" project (FP-7-REGPOT 2012-2013-1, Grant agreement no. FP7-316265). The validation cohort recruitment was funded by a grant from Fundacio de la Marato TV3 2012 (785/U/2013). The funding institutions had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication

Development and external validation of a faecal immunochemical test-based prediction model for colorectal cancer detection in symptomatic patients

Background: risk prediction models for colorectal cancer (CRC) detection in symptomatic patients based on available biomarkers may improve CRC diagnosis. Our aim was to develop, compare with the NICE referral criteria and externally validate a CRC prediction model, COLONPREDICT, based on clinical and laboratory variables. Methods: this prospective cross-sectional study included consecutive patients with gastrointestinal symptoms referred for colonoscopy between March 2012 and September 2013 in a derivation cohort and between March 2014 and March 2015 in a validation cohort. In the derivation cohort, we assessed symptoms and the NICE referral criteria, and determined levels of faecal haemoglobin and calprotectin, blood haemoglobin, and serum carcinoembryonic antigen before performing an anorectal examination and a colonoscopy. A multivariate logistic regression analysis was used to develop the model with diagnostic accuracy with CRC detection as the main outcome. Results: we included 1572 patients in the derivation cohort and 1481 in the validation cohorts, with a 13.6 % and 9.1 % CRC prevalence respectively. The final prediction model included 11 variables: age (years) (odds ratio [OR] 1.04, 95 % confidence interval [CI] 1.02-1.06), male gender (OR 2.2, 95 % CI 1.5-3.4), faecal haemoglobin ≥20 μg/g (OR 17.0, 95 % CI 10.0-28.6), blood haemoglobin <10 g/dL (OR 4.8, 95 % CI 2.2-10.3), blood haemoglobin 10-12 g/dL (OR 1.8, 95 % CI 1.1-3.0), carcinoembryonic antigen ≥3 ng/mL (OR 4.5, 95 % CI 3.0-6.8), acetylsalicylic acid treatment (OR 0.4, 95 % CI 0.2-0.7), previous colonoscopy (OR 0.1, 95 % CI 0.06-0.2), rectal mass (OR 14.8, 95 % CI 5.3-41.0), benign anorectal lesion (OR 0.3, 95 % CI 0.2-0.4), rectal bleeding (OR 2.2, 95 % CI 1.4-3.4) and change in bowel habit (OR 1.7, 95 % CI 1.1-2.5). The area under the curve (AUC) was 0.92 (95 % CI 0.91-0.94), higher than the NICE referral criteria (AUC 0.59, 95 % CI 0.55-0.63; p < 0.001). On the basis of the thresholds with 90 % (5.6) and 99 % (3.5) sensitivity, we divided the derivation cohort into three risk groups for CRC detection: high (30.9 % of the cohort, positive predictive value [PPV] 40.7 %, 95 % CI 36.7-45.9 %), intermediate (29.5 %, PPV 4.4 %, 95 % CI 2.8-6.8 %) and low (39.5 %, PPV 0.2 %, 95 % CI 0.0-1.1 %). The discriminatory ability was equivalent in the validation cohort (AUC 0.92, 95 % CI 0.90-0.94; p = 0.7). Conclusions: COLONPREDICT is a highly accurate prediction model for CRC detection

Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing

SUPPLEMENTARY MATERIAL accompanies this paper athttp://links.lww.com/CTG/A114OBJECTIVES: Serrated polyposis syndrome (SPS) is a complex disorder with a high risk of colorectal cancer for which the germline factors remain largely unknown. Here, we combined whole-exome sequencing (WES) and linkage studies in families with multiple members affected by SPS to identify candidate genes harboring rare variants with higher penetrance effects. METHODS: Thirty-nine affected subjects from 16 extended SPS families underwent WES. Genome-wide linkage analysis was performed under linear and exponential models. The contribution of rare coding variants selected to be highly pathogenic was assessed using the gene-based segregation test. RESULTS: significant linkage peak was identified on chromosome 3p25.2-p22.3 (maxSNP = rs2293787; LODlinear = 2.311, LODexp = 2.11), which logarithm of the odds (LOD) score increased after fine mapping for the same marker (maxSNP = rs2293787; LODlinear = 2.4, LODexp = 2.25). This linkage signal was replicated in 10 independent sets of random markers from this locus. To assess the contribution of rare variants predicted to be pathogenic, we performed a family-based segregation test with 11 rare variants predicted to be deleterious from 10 genes under the linkage intervals. This analysis showed significant segregation of rare variants with SPS in CAPT7, TMEM43, NGLY1, and FBLN2 genes (weighted Pvalue > 0.007). DISCUSSION: Protein network analysis suggested FBLN2 as the most plausible candidate genes for germline SPS predisposition. Etiologic rare variants implicated in disease predisposition may be identified by combining traditional linkage with WES data. This powerful approach was effective for the identification of a new candidate gene for hereditary SPS.M.D.-G. was supported by a contract from Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (Generalitat de Catalunya, 2018FI_B1_00213). S.F.-E., C.A.-C. and J.M. were supported by a contract from CIBEREHD. Y.S.L. was supported by a fellowship (LCF/BQ/DI18/11660058) from "la Caixa" Foundation (ID 100010434) funded EU Horizon 2020 Programme (Marie Sklodowska-Curie grant agreement no. 713673). LB was supported by a Juan de la Cierva postdoctoral contract (FJCI-2017-32593). CIBEREHD and CIBERONC are funded by the Instituto de Salud Carlos III. CT, BJO, and JMF were supported by Australian National Health and Medical Research (NHMRC) Project Grants 1063960 and 1066177. This research was supported by grants from Fondo de Investigacion Sanitaria/FEDER (16/00766, 17/00878), Fundacion Cientifica de la Asociacion Espanola contra el Cancer (GCB13131592CAST), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Programme (Generalitat de Catalunya), and Agencia de Gestio d'Ajuts Universitaris i de Recerca (Generalitat de Catalunya, GRPRE 2017SGR21, GRC 2017SGR653). This article is based on work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology). www.cost.eu.Potential competing interests: None to report

Colorectal Cancer Genetic Variants Are Also Associated with Serrated Polyposis Syndrome Susceptibility

Background Serrated polyposis syndrome (SPS) is a clinical entity characterised by large and/ormultiple serrated polyps throughout the colon and increased risk for colorectal cancer (CRC). The basis for SPS genetic predisposition is largely unknown. Common, low-penetrance genetic variants have been consistently associated with CRC susceptibility, however, their role in SPS genetic predisposition has not been yet explored. Objective The aim of this study was to evaluate if common, low-penetrance genetic variants for CRC risk are also implicated in SPS genetic susceptibility. Methods A case-control study was performed in 219 SPS patients and 548 asymptomatic controls analysing 65 CRC susceptibility variants. A risk prediction model for SPS predisposition was developed. Results Statistically significant associations with SPS were found for seven genetic variants (rs4779584-GREM1, rs16892766-EIF3H, rs3217810-CCND2, rs992157-PNKD1/TMBIM1, rs704017-ZMIZ1, rs11196172-TCF7L2, rs6061231-LAMA5). TheGREM1risk allele was remarkably over-represented in SPS cases compared with controls (OR=1.573, 1.21-2.04, p value=0.0006). A fourfold increase in SPS risk was observed when comparing subjects within the highest decile of variants (>= 65) with those in the first decile (<= 50). Conclusions Genetic variants for CRC risk are also involved in SPS susceptibility, being the most relevant ones rs4779584-GREM1, rs16892766-EIF3Hand rs3217810-CCND2.CA--C, JM and JJL were supported by a contract from CIBEREHD. YSdL was supported by a fellowship (LCF/BQ/DI18/11660058) from 'la Caixa' Foundation (ID 100010434) funded EU Horizon 2020 Programme (Marie Sklodowska-Curie grant agreement no. 713673). LB was supported by a Juan de la Cierva postdoctoral contract (FJCI-2017-32593) and MD-G by a contract from Agencia de Gestio d'Ajuts Universitaris i de Recerca, AGAUR, (Generalitat de Catalunya, 2018FI_B1_00213). CIBEREHD, CIBERER, CIBERESP and CIBERONC are funded by the Instituto de Salud Carlos III. This research was supported by grants from Fondo de Investigacion Sanitaria/FEDER (14/00613, 16/00766, 17/00509, 17/00878), Fundacion Cientifica de la Asociacion Espanola contra el Cancer (GCB13131592CAST), Spanish Ministry of Science, Innovation and Universities, co-funded by FEDER funds, (SAF201680888--R), PERIS (SLT002/16/00398, SLT002/16/0037, Generalitat de Catalunya), CERCA Programme (Generalitat de Catalunya) and Agencia de Gestio d'Ajuts Universitaris i de Recerca (Generalitat de Catalunya, GRPRE 2017SGR21, GRC 2017SGR653, 2017SGR1282, 2017SGR723). This article is based upon work from COST Action CA17118, supported by European Cooperation in Science and Technology (COST). www.cost.eu

Colorectal cancer genetic variants are also associated with serrated polyposis syndrome susceptibility

Background: Serrated polyposis syndrome (SPS) is a clinical entity characterised by large and/ormultiple serrated polyps throughout the colon and increased risk for colorectal cancer (CRC). The basis for SPS genetic predisposition is largely unknown. Common, low-penetrance genetic variants have been consistently associated with CRC susceptibility, however, their role in SPS genetic predisposition has not been yet explored. Objective: The aim of this study was to evaluate if common, low-penetrance genetic variants for CRC risk are also implicated in SPS genetic susceptibility. Methods: A case-control study was performed in 219 SPS patients and 548 asymptomatic controls analysing 65 CRC susceptibility variants. A risk prediction model for SPS predisposition was developed. Results: Statistically significant associations with SPS were found for seven genetic variants (rs4779584-GREM1, rs16892766-EIF3H, rs3217810-CCND2, rs992157-PNKD1/TMBIM1, rs704017-ZMIZ1, rs11196172-TCF7L2, rs6061231-LAMA5). The GREM1 risk allele was remarkably over-represented in SPS cases compared with controls (OR=1.573, 1.21-2.04, p value=0.0006). A fourfold increase in SPS risk was observed when comparing subjects within the highest decile of variants (≥65) with those in the first decile (≤50). Conclusions: Genetic variants for CRC risk are also involved in SPS susceptibility, being the most relevant ones rs4779584-GREM1, rs16892766-EIF3H and rs3217810-CCND2

Clinical and Pathological Characterization of Lynch-Like Syndrome

Background & aims: Lynch syndrome is characterized by DNA mismatch repair (MMR) deficiency. Some patients with suspected Lynch syndrome have DNA MMR deficiencies but no detectable mutations in genes that encode MMR proteins-this is called Lynch-like syndrome (LLS). There is no consensus on management of patients with LLS. We collected data from a large series of patients with LLS to identify clinical and pathology features. Methods: We collected data from a nationwide-registry of patients with colorectal cancer (CRC) in Spain. We identified patients whose colorectal tumors had loss of MSH2, MSH6, PMS2, or MLH1 (based on immunohistochemistry), without the mutation encoding V600E in BRAF (detected by real-time PCR), and/or no methylation at MLH1 (determined by methylation-specific multiplex ligation-dependent probe amplification), and no pathogenic mutations in MMR genes, BRAF, or EPCAM (determined by DNA sequencing). These patients were considered to have LLS. We collected data on demographic, clinical, and pathology features and family history of neoplasms. The χ2 test was used to analyze the association between qualitative variables, followed by the Fisher exact test and the Student t test or the Mann-Whitney test for quantitative variables. Results: We identified 160 patients with LLS; their mean age at diagnosis of CRC was 55 years and 66 patients were female (41%). The Amsterdam I and II criteria for Lynch syndrome were fulfilled by 11% of cases and the revised Bethesda guideline criteria by 65% of cases. Of the patients with LLS, 24% were identified in universal screening. There were no proportional differences in sex, indication for colonoscopy, immunohistochemistry, pathology findings, or personal history of CRC or other Lynch syndrome-related tumors between patients who met the Amsterdam and/or Bethesda criteria for Lynch syndrome and patients identified in universal screening for Lynch syndrome, without a family history of CRC. Conclusions: Patients with LLS have homogeneous clinical, demographic, and pathology characteristics, regardless of family history of CRC